AKYNZEO 300mg / 0.5mg capsules medication leaflet

Akynzeo 300 mg/0.5 mg hard capsules

Each hard capsule contains 300 mg of netupitant and palonosetron hydrochloride equivalent to 0.5 mgof palonosetron.

Each hard capsule contains 7 mg of sorbitol (E420) and 20 mg of sucrose.

It may also contain a trace of lecithin derived from soya.

For the full list of excipients, see section 6.1.

Hard capsule

Opaque gelatin capsule of size “0” (length 21.7 mm) with white body and caramel cap with “HE1”printed on the body. The hard capsule is filled with three tablets and one soft capsule.

Akynzeo is indicated in adults for the:

- Prevention of acute and delayed nausea and vomiting associated with highly emetogeniccisplatin-based cancer chemotherapy.

- Prevention of acute and delayed nausea and vomiting associated with moderately emetogeniccancer chemotherapy.

One 300 mg/0.5 mg capsule should be administered approximately one hour prior to the start of eachchemotherapy cycle.

The recommended oral dexamethasone dose should be reduced by approximately 50 % when co-administered with netupitant/palonosetron capsules (see section 4.5 and clinical studies administrationschedule in section 5.1).

Elderly people

No dosage adjustment is necessary for elderly patients. Caution should be exercised when using thismedicinal product in patients over 75 years, due to the long half-life of the active substances and thelimited experience in this population.

Dosage adjustment is not considered necessary in patients with mild to severe renal impairment. Renalexcretion for netupitant is negligible. Mild to moderate renal impairment does not significantly affectpalonosetron pharmacokinetic parameters. Total systemic exposure to intravenous palonosetronincreased by approximately 28% in severe renal impairment relative to healthy subjects. Thepharmacokinetics of palonosetron or netupitant has not been studied in subjects with end-stage renaldisease requiring hemodialysis and no data on the effectiveness or safety of netupitant/palonosetroncapsules in these patients are available. Therefore, use in these patients should be avoided.

No dosage adjustment is necessary for patients with mild or moderate hepatic impairment (Child-

Pugh score 5-8). Limited data exist in patients with severe hepatic impairment (Child Pugh score ≥9). As use in patients with severe hepatic impairment may be associated with increased exposure ofnetupitant, this medicinal product should be used with caution in these patients (see sections 4.4and 5.2).

The safety and efficacy of Akynzeo capsules in the paediatric population have not been established.

No data are available.

For oral use.

The hard capsule should be swallowed whole and not opened as it contains 4 single pharmaceuticalcomponents that should be administered at the same time.

It can be taken with or without food.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

As palonosetron may increase large bowel transit time, patients with a history of constipation orsigns of subacute intestinal obstruction should be monitored following administration (seesection 4.8).

Serotonin syndrome

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone or incombination with other serotonergic medicinal products (including selective serotonin reuptakeinhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observationof patients for serotonin syndrome-like symptoms is advised (see section 4.8).

QT Prolongation

An ECG study was conducted in adult male and female healthy volunteers with oral netupitant either200 or 600 mg administered in combination with oral palonosetron 0.5 or 1.5 mg, respectively. Thestudy demonstrated no clinically important effects on ECG parameters: the largest point estimate ofthe placebo and baseline corrected QTc interval was 7.0 ms (one-sided upper 95% confidencelimit 8.8 ms), observed 16 hours after the administration of supratherapeutic doses (600 mgnetupitant and 1.5 mg palonosetron). Upper 95% confidence limit of the point estimates of placeboand baseline corrected QTcI was constantly within 10 ms at all time points over 2 days after studysubstance administration.

However, since netupitant/palonosetron capsules contains a 5-HT3 receptor antagonist, caution shouldbe exercised in concomitant use with medicinal products that increase the QT interval or in patientswho have or are likely to develop prolongation of the QT interval. These conditions include patientswith a personal or family history of QT prolongation, electrolyte abnormalities, congestive heartfailure, bradyarrhythmia, conduction disturbances and in patients taking anti-arrhythmic medicinalproducts or other medicinal products that lead to QT prolongation or electrolyte abnormalities.

Hypokalaemia and hypomagnesaemia should be corrected prior to administration.

Caution should be exercised in patients with severe hepatic impairment since limited data areavailable in these patients.

This medicinal product should be used with caution in patients receiving concomitant orallyadministered active substances that are metabolised primarily through CYP3A4 and with a narrowtherapeutic range (see section 4.5).

Chemotherapeutic agents that are substrates for CYP3A4

Netupitant is a moderate inhibitor of CYP3A4 and can increase the exposure of chemotherapeuticagents that are substrates for CYP3A4 e.g. docetaxel (see section 4.5). Therefore, patients should bemonitored for increased toxicity of chemotherapeutic agents that are substrates for CYP3A4,including irinotecan. Furthermore, netupitant may also affect the efficacy of chemotherapeutic agentsthat need activation by CYP3A4 metabolism.

This medicinal product contains 7 mg of sorbitol (E420) in each hard capsule.

The additive effect of concomitantly administered medicinal products containing sorbitol (E 420) (orfructose) and dietary intake of sorbitol (E 420) (or fructose) should be taken into account.

The content of sorbitol (E 420) in medicinal products for oral use may affect the bioavailability ofother medicinal products for oral use administered concomitantly.

This medicinal product also contains 20 mg of sucrose in each capsule. Patients with rare hereditaryproblems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiencyshould not take this medicinal product.

This medicinal product contains less than 1 mmol sodium per (23 mg) per hard capsule, that is tosay essentially ‘sodium-free’.

It may also contain a trace of lecithin derived from soya. Therefore, patients with knownhypersensitivity to peanut or soya should be monitored closely for signs of an allergic reaction (seesection 4.8).

When netupitant/palonosetron capsules are used concomitantly with another CYP3A4 inhibitor,netupitant plasma concentrations could be elevated. When this medicinal product is usedconcomitantly with medicinal products that induce CYP3A4 activity, netupitant plasma concentrationscould be reduced and this may result in decreased efficacy. This medicinal product can increaseplasma concentrations of concomitantly administered medicinal products that are metabolised via

In humans, netupitant is eliminated mainly by hepatic metabolism mediated by CYP3A4 with amarginal renal excretion. At a dose of 300 mg in humans, netupitant is a substrate and moderateinhibitor of CYP3A4. Palonosetron is eliminated from the body through both renal excretion andmetabolic pathways, with the latter mediated via multiple CYP enzymes. Palonosetron is mainlymetabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2 isoenzymes. Based onin vitro studies, palonosetron does not inhibit or induce cytochrome P450 isoenzyme at clinicallyrelevant concentrations.

Interaction between oral netupitant and oral palonosetron:

No clinically relevant pharmacokinetic interactions have been observed between oral netupitant andoral palonosetron.

Interaction with CYP3A4 substrates:

Dexamethasone

Co-administration of a single dose of 300 mg netupitant with a dexamethasone regimen (20 mg on

Day 1, followed by 8 mg twice daily from Day 2 to Day 4) significantly increased the exposure todexamethasone in a time and dose dependent manner. The AUC0-24 (Day 1), the AUC24-36 (Day 2)and the AUC84-108 and AUC84-∞ (Day 4) of dexamethasone increased 2.4-fold, with co-administrationof 300 mg netupitant. The pharmacokinetic profile of netupitant was unchanged when administeredin combination with dexamethasone.

As such, the oral dexamethasone dose should be reduced by approximately 50% when co-administeredwith netupitant/palonosetron capsules (see section 4.2).

Chemotherapeutic medicinal products (docetaxel, etoposide, cyclophosphamide)

Exposure to docetaxel and etoposide was increased 37% and 21%, respectively, when co-administeredwith netupitant/palonosetron capsules. No consistent effect was seen with cyclophosphamide afternetupitant co-administration.

Netupitant/palonosetron capsules, when given with a single oral dose of 60 μg ethinylestradiol and300 μg levonorgestrel had no significant effect on the AUC of ethinylestradiol and increased the AUCof levonorgestrel by 1.4-fold; clinical effects on the efficacy of hormonal contraception are unlikely.

No relevant changes of netupitant and palonosetron pharmacokinetics were observed.

Erythromycin and Midazolam

Exposure to erythromycin and midazolam was increased approximately 1.3 and 2.4 fold, respectively,when each was co-administered with netupitant. These effects were not considered clinicallyimportant. The pharmacokinetic profile of netupitant was unaffected by the concomitantadministration of either midazolam or erythromycin. The potential effects of increased plasmaconcentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam,triazolam) should be considered when coadministering these active substances withnetupitant/palonosetron capsules.

Serotonergic medicinal products (e.g. SSRIs and SNRIs)

There have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists andother serotonergic medicinal products (including SSRIs such as fluoxetine, paroxetine, sertraline,fluvoxamine, citalopram or escitalopram and SNRIs such as venlafaxine or duloxetine) (seesection 4.4).

Effect of other medicinal products on the pharmacokinetics of Akynzeo

Netupitant is mainly metabolised by CYP3A4; therefore, co-administration with medicinal productsthat inhibit or induce CYP3A4 activity may influence plasma concentrations of netupitant.

Consequently, concomitant administration with strong CYP3A4 inhibitors (e.g., ketoconazole)should be approached with caution and concomitant administration with strong CYP3A4 inducers(e.g., rifampicin) should be avoided. Moreover, this medicinal product should be used with caution inpatients receiving concomitant orally administered active substances with a narrow therapeutic rangethat are primarily metabolised by CYP3A4, such as cyclosporine, tacrolimus, sirolimus, everolimus,alfentanil, diergotamine, ergotamine, fentanyl, and quinidine.

Effect of ketoconazole and rifampicin

Administration of the CYP3A4 inhibitor ketoconazole with netupitant/palonosetron capsules increasedthe AUC of netupitant 1.8 fold and Cmax 1.3 fold when compared to the administration ofnetupitant/palonosetron capsules alone. Co-administration with ketoconazole did not affect thepharmacokinetics of palonosetron.

Administration of the CYP3A4 inducer rifampicin with Akynzeo alone decreased the AUC ofnetupitant 5.2 fold and Cmax 2.6 fold. Co-administration of rifampicin did not affect thepharmacokinetics of palonosetron. Consequently, concomitant administration with strong CYP3A4inhibitors (e.g., ketoconazole) should be approached with caution and concomitant administrationwith strong CYP3A4 inducers (e.g. rifampicin) should be avoided.

Additional interactions

Netupitant/palonosetron capsules are unlikely to interact with medicinal products which are P-gpsubstrates. Netupitant is not a substrate for P-gp. When netupitant was administered on Day 8 of a12-day regimen of digoxin, no changes in digoxin pharmacokinetics were observed.

Inhibition of the efflux transported BCRP and glucuronidation isozyme UGT2B7 by netupitant andits metabolites is unlikely and, if it occurs, of scarce clinical relevance.

In vitro data shows that netupitant inhibits UGT2B7, the magnitude of such an effect in the clinicalsetting is not established. Caution is recommended when netupitant is combined with an oralsubstrate of this enzyme (e.g.zidovudine, valproic acid, morphine).

In vitro data suggests that netupitant inhibits the efflux of transporter BCRP. The clinical relevanceof this effect is not established.

In vitro data show that netupitant is a P-gp inhibitor. In a study performed in healthy volunteers,netupitant does not affect the exposure of digoxin, a P-gp substrate, whereas it increases its Cmax by1.09 fold [90%CI 0.9-1.31]. It is not excluded that this effect may be more marked, and then clinicallyrelevant, in cancer patients, notably those having abnormal renal function. Therefore, caution isrecommended when netupitant is combined with digoxin or with other P-gp substrates such asdabigatran, or colchicine.

Women of childbearing potential/ contraception in females

Women of childbearing potential should not be pregnant or become pregnant while on treatment withnetupitant/palonosetron capsules. A pregnancy test should be performed on all pre-menopausal womenprior to treatment. Women of childbearing potential must use effective contraception during therapyand up to one month after treatment with this medicinal product.

Netupitant

There are no data about the use of netupitant in pregnant women. Studies in animals have shownreproductive toxicity including teratogenic effects in rabbit without safety margin (see section 5.3).

Palonosetron

There are no data about the use of palonosetron in pregnant women. Animal data do not indicatedirect or indirect harmful effects of palonosetron with the respect to reproductive toxicity (seesection 5.3).

Netupitant/palonosetron capsules are contraindicated during pregnancy (see section 4.3).

It is unknown whether palonosetron or netupitant are excreted in human milk. A risk to the sucklingchild cannot be excluded. Netupitant/palonosetron capsules should not be used during breast-feeding.

Breast-feeding should be discontinued during treatment with this medicinal product and for 1 monthafter the last dose.

Netupitant

No effect on fertility has been observed in animal studies.

Palonosetron

Degeneration of seminiferous epithelium has been observed in rat study (see section 5.3).

Netupitant/palonosetron capsules have moderate influence on the ability to drive and use machines.

Since it may induce dizziness, somnolence or fatigue, patients should be cautioned not to drive or usemachines if such symptoms occur.

Common adverse reactions reported with netupitant/palonosetron capsules were headache (3.6%),constipation (3.0%) and fatigue (1.2%).

Adverse reactions are listed below by MedDRA body system organ class and frequency.

The following convention has been used for classification of frequency:

Very common (≥1/10),

Common (≥1/100 to <1/10),

Uncommon (≥1/1 000 to <1/100),

Rare (≥1/10 000 to <1/1 000),

Very rare (<1/10 000),

Not known (cannot be estimated from the available data).

Table1: Adverse reactions

System organ class Common Uncommon Rare

Infections and Cystitisinfestations

Blood and lymphatic Neutropenia Leukopeniasystem disorders Leucocytosis Lymphocytosis

Metabolism and Decreased appetite Hypokalaemianutrition disorders

Psychiatric disorders Insomnia Acute psychosis

Mood altered

Sleep disorder

Nervous system Headache Dizziness Hypoaesthesiadisorders Somnolence

Eye disorders Conjunctivitis

Vision blurred

Ear and labyrinth Vertigo Tinnitusdisorders

Cardiac disorders Atrioventricular Arrhythmiablock first degree

Cardiomyopathy Atrioventricular block seconddegree

Conduction disorder Bundle branch block left

Tachycardia Bundle branch block right

Mitral valve incompetence

Myocardial ischaemia

Ventricular extrasystoles

Vascular disorders Hypertension Flushing

Respiratory, thoracic Hiccupsand mediastinaldisorders

Gastrointestinal Constipation Abdominal Dry mouthdisorders distension

Abdominal pain Dysphagia

Diarrhoea Eructation

Dyspepsia Haemorrhoids

Flatulence Tongue coated

Nausea Vomiting

Skin and subcutaneous Alopecia Erythematissue disorders Urticaria Pruritus

Musculoskeletal and Back painconnective tissue Pain in extremitiesdisorders

General disorders and Fatigue Asthenia Feeling hotadministration siteconditions Non-cardiac chest pain

Product taste abnormal

Investigations Liver transaminases Blood bilirubin increasedincreased

Blood alkaline Blood creatine phosphokinasephosphatase increasedincreased

Blood creatinine Blood creatine phosphokinaseincreased MB increased

Electrocardiogram Blood urea increased

QT prolonged

Electrocardiogram ST segmentdepression

Electrocardiogram ST-Tsegment abnormal

Myoglobin blood increased

Neutrophil count increased

Troponin increased

Post-marketing data indicates that the adverse reactions profile is generally similar to that seen inclinical trials.

Netupitant:

No common adverse reactions are attributable to netupitant, the new component of the fixedcombination.

Palonosetron:

Cases of constipation with faecal impaction requiring hospitalisation have been reported inassociation with palonosetron 0.75 mg.

In addition, eye swelling, dyspnoea and myalgia as adverse reactions have been reported with oralpalonosetron but not observed during the development of this medicinal product. All these reactionswere uncommon.

Very rare cases of anaphylaxis, anaphylactic/anaphylactoid reactions and shock have been reportedfrom the post-marketing use of intravenous palonosetron. The signs may include hives, itch,angioedema, low blood pressure, throat tightness, chest tightness, dyspnoea, loss of consciousness.

There have also been reports of serotonin syndrome. The signs may include tremor, agitation,sweating, myoclonic movements, hypertonia and fever.

Netupitant and palonosetron combinate capsule:

This medicinal product may contain a trace of lecithin derived from soya. Therefore, patients withknown hypersensitivity to peanut or soya should be monitored closely for signs of an allergic reaction.

The signs may include hives, skin rash, itching, difficulty breathing or swallowing, swollen mouth,face, lips, tongue or throat and sometimes a drop-in blood pressure.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Based on the experience with healthy subjects exposed to oral netupitant 600 mg in combination withpalonosetron 1.50 mg the potential acute symptoms of overdose are headache, dizziness,constipation, anxiety, palpitations, euphoric mood and pain in the legs. In case of overdose, themedicinal product should be discontinued and general supportive treatment and monitoring should beprovided. Because of the antiemetic activity of netupitant and palonosetron, emesis induced by amedicinal product may not be effective. Dialysis studies have not been performed. However, due tothe large volume of distribution of palonosetron and netupitant, dialysis is unlikely to be an effectivetreatment for overdose.

Pharmacotherapeutic group: Antiemetics and antinauseants, serotonin (5-HT3) antagonists; ATCcode: A04AA55

Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors.

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and littleor no affinity for other receptors. Chemotherapeutic substances produce nausea and vomiting bystimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotoninthen activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.

Delayed emesis has been associated with the activation of tachykinin family neurokinin 1 (NK1)receptors (broadly distributed in the central and peripheral nervous systems) by substance P. Asshown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.

Netupitant was shown to cross the blood brain barrier with a NK1 receptor occupancy of 92.5%,86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, afteradministration of 300 mg netupitant.

Oral administration of Akynzeo in combination with dexamethasone has been shown to prevent acuteand delayed nausea and vomiting associated with highly and moderately emetogenic cancerchemotherapy in two separate pivotal studies.

Highly Emetogenic Chemotherapy (HEC) study

In a multicenter, randomized, parallel, double-blind, controlled clinical study of 694 patients, theefficacy and safety of single doses of oral netupitant in combination with oral palonosetron wascompared with a single oral dose of palonosetron in cancer patients receiving a chemotherapyregimen that included cisplatin (median dose = 75 mg/m2). The efficacy of Akynzeo was assessed in135 patients who received a single oral dose (netupitant 300 mg and palonosetron 0.5 mg) and136 patients who received oral palonosetron 0.5 mg alone.

Treatment regimens for the Akynzeo and the palonosetron 0.5 mg arms are displayed in Table below.

Table 2: Oral antiemetic treatment regimen -- HEC study

Treatment regimen Day 1 Days 2 to 4

Akynzeo Akynzeo (Netupitant 300 mg + Dexamethasone 8 mg once

Palonosetron 0.5 mg) a day

Dexamethasone 12 mg

Palonosetron Palonosetron 0.5 mg Dexamethasone 8 mg twice

Dexamethasone 20 mg a day

The primary efficacy endpoint was complete response (CR) rate (defined as no emetic episodes, norescue medication) within 120 hours (overall phase) after the start of the highlyemetogenic chemotherapy administration.

A summary of the key results from this study is shown in Table 3 below.

Table 3: Proportion of patients receiving cisplatin chemotherapy responding by treatmentgroup and phase

Palonosetron

Akynzeo 0.5 mg

N=135 N=136% % p-value

Primary endpoint

Complete response

Overall phase§ 89.6 76.5 0.004

Major secondary endpoints

Complete response

Acute phase‡ 98.5 89.7 0.007

Delayed phase† 90.4 80.1 0.018

No emesis

Acute phase 98.5 89.7 0.007

Delayed phase 91.9 80.1 0.006

Overall phase 91.1 76.5 0.001

No significant nausea

Acute phase 98.5 93.4 0.050

Delayed phase 90.4 80.9 0.004

Overall phase 89.6 79.4 0.021‡Acute phase: 0 to 24 hours post-cisplatin treatment.†Delayed phase: 25 to 120 hours post-cisplatin treatment.§Overall: 0 to 120 hours post-cisplatin treatment.

Moderately Emetogenic Chemotherapy (MEC) study

In a multicenter, randomized, parallel, double-blind, active-controlled, superiority study, the efficacyand safety of a single oral dose of Akynzeo was compared with a single oral dose of palonosetron0.5 mg in cancer patients scheduled to receive the first cycle of an anthracycline and cyclophosphamideregimen for the treatment of a solid malignant tumour. At the time of the study, anthracycline-cyclophosphamide containing chemotherapy regimens were considered to be moderately emetogenic.

Recent guidance has updated these regimens to highly emetogenic.

All patients received a single oral dose of dexamethasone.

Table 4: Oral antiemetic treatment regimen - MEC study

Treatment Day 1 Days 2 to 3regimen

Akynzeo Akynzeo Netupitant 300 mg No antiemetic treatment

Palonosetron 0.5 mg

Dexamethasone 12 mg

Palonosetron Palonosetron 0.5 mg No antiemetic treatment

Dexamethasone 20 mg

After completion of cycle 1, patients had the option to participate in a multiple-cycle extension,receiving the same treatment as assigned in cycle 1. There was no pre-specified limit of the numberof repeat consecutive cycles for any patient. A total of 1450 patients (Akynzeo n=725; Palonosetronn=725) received study medication. Of these, 1438 patients (98.8%) completed cycle 1 and1286 patients (88.4%) continued treatment in the multiple-cycle extension. A total of 907 patients(62.3%) completed the multiple-cycle extension up to a maximum of eight treatment cycles.

A total of 724 patients (99.9%) were treated with cyclophosphamide. All patients were additionallytreated with either doxorubicin (68.0%) or epirubicin (32.0%).

The primary efficacy endpoint was the CR rate in the delayed phase, 25-120 hours after the start ofthe chemotherapy administration.

A summary of the key results from this study is shown in Table below.

Table 5: Proportion of patients receiving anthracycline and cyclophosphamide chemotherapyresponding by treatment group and phase - cycle 1

Akynzeo Palonosetron0.5 mg

N=724 N=725% % p-value*

Primary endpoint

Complete response

Delayed phase† 76.9 69.5 0.001

Major secondary endpoints

Complete response

Acute phase‡ 88.4 85.0 0.047

Overall phase§ 74.3 66.6 0.001

No emesis

Acute phase 90.9 87.3 0.025

Delayed phase 81.8 75.6 0.004

Overall phase 79.8 72.1 <0.001

No significant nausea

Acute phase 87.3 87.9 N.S.

Delayed phase 76.9 71.3 0.014

Overall phase 74.6 69.1 0.020

* p-value from Cochran-Mantel-Haenszel test, stratified by age class and region.‡Acute phase: 0 to 24 hours after anthracycline and cyclophosphamide regimen†Delayed phase: 25 to 120 hours after anthracycline and cyclophosphamide regimen§Overall: 0 to 120 hours after anthracycline and cyclophosphamide regimen

Patients continued into the Multiple-Cycle extension for up to 7 additional cycles of chemotherapy.

Antiemetic activity of Akynzeo was maintained throughout repeat cycles for those patientscontinuing in each of the multiple cycles.

The impact of nausea and vomiting on patients’ daily lives was assessed using the Functional Living

Index-Emesis (FLIE). The proportion of patients with Overall no impact on daily life was 6.3%higher (p value =0.005) in the Akynzeo group (78.5%) than in the palonosetron group (72.1%).

Multiple-cycle safety study in patients receiving either Highly Emetogenic Chemotherapy or

Moderately Emetogenic Chemotherapy

In a separate study, a total of 413 patients undergoing initial and repeat cycles of chemotherapy(including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens), were randomized to receiveeither Akynzeo (n=309) or aprepitant and palonosetron (n=104). Safety and efficacy were maintainedthroughout all cycles.

The European Medicines Agency has waived the obligation to submit the results of studies with

Akynzeo in all subsets of the paediatric population in prevention of acute and delayed nausea andvomiting associated with highly emetogenic cisplatin-based and moderately emetogenic cancerchemotherapy (see section 4.2 for information on paediatric use).

Netupitant

Absolute netupitant bioavailability data are not available in humans; based on data from two studieswith intravenous netupitant, the bioavailability in humans is estimated to be greater than 60%.

In single dose oral studies, netupitant was measurable in plasma between 15 minutes and 3 hoursafter dosing. Plasma concentrations followed a first order absorption process and reached Cmax inapproximately 5 hours. There was a supra-proportional increase in Cmax and AUC parameters fordoses from 10 mg to 300 mg.

In 82 healthy subjects given a single oral dose of netupitant 300 mg, maximum plasma netupitantconcentration (Cmax) was 486 ±268 ng/mL (mean ± SD) and median time to maximum concentration(Tmax) was 5.25 hours, the AUC was 15032 ± 6858 h.ng/mL. In a pooled analysis, females had ahigher netupitant exposure compared to males; there was a 1.31-fold increase in Cmax, a 1.02 foldincrease for AUC and a 1.36 fold increase in half-life.

Netupitant AUC0-∞ and Cmax increased by 1.1 fold and 1.2 fold, respectively, after a high fat meal.

Palonosetron

Following oral administration, palonosetron is well absorbed with its absolute bioavailabilityreaching 97%. After single oral doses using buffered solution mean maximum palonosetronconcentrations (Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportionalover the dose range of 3.0 to 80 mcg/kg in healthy subjects.

In 36 healthy male and female subjects given a single oral dose of 0.5 mg palonosetron, maximumplasma concentration (Cmax) was 0.81 ± 1.66 ng/mL (mean ± SD) and time to maximumconcentration (Tmax) was 5.1 ± 1.7 hours. In female subjects (n=18), the mean AUC was 35% higherand the mean Cmax was 26% higher than in male subjects (n=18). In 12 cancer patients given a singleoral dose of palonosetron 0.5 mg one hour prior to chemotherapy, Cmax was 0.93 ± 0.34 ng/mL and

Tmax was 5.1 ± 5.9 hours. The AUC was 30% higher in cancer patients than in healthy subjects. Ahigh fat meal did not affect the Cmax and AUC of oral palonosetron.

Netupitant

After a single oral 300 mg dose administration in cancer patients, netupitant disposition wascharacterised by a two compartment model with an estimated median systemic clearance of 20.5 L/hand a large distribution volume in the central compartment (486 L). Human plasma protein bindingof netupitant and its two major metabolites M1 and M3 is > 99% at concentrations ranging from 10to 1500 ng/mL. The third major metabolite, M2, is > 97% bound to plasma proteins.

Palonosetron

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% ofpalonosetron is bound to plasma proteins.

Netupitant

Three metabolites have been detected in human plasma at netupitant oral doses of 30 mg and higher(the desmethyl derivative, M1; the N-oxide derivative, M2; the OH-methyl derivative, M3). In vitrometabolism studies have suggested that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 areinvolved in the metabolism of netupitant. After administration of a single oral dose of 300 mgnetupitant, mean plasma netupitant/plasma radioactivity ratios ranged from 0.13 to 0.49 over 96 hpost-dose. The ratios were time dependent with values decreasing gradually beyond 24 h post-dose,indicating that netupitant is being rapidly metabolised. Mean Cmax was approximately 11%, 47% and16% of the parent for M1, M2 and M3 respectively; M2 had the lowest AUC relative to the parent(14%) whereas M1 and M3 AUC were approximately 29% and 33% of the parent, respectively. M1,

M2 and M3 metabolites were all shown to be pharmacologically active in an animalpharmacodynamic model, where M3 was most potent and M2 least active.

Palonosetron

Palonosetron is eliminated by multiple routes with approximately 50% metabolised to form twoprimary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites eachhave less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolismstudies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved inthe metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantlydifferent between poor and extensive metabolizers of CYP2D6 substrates.

Netupitant

Following administration of a single dose of Akynzeo, netupitant is eliminated from the body in amulti-exponential fashion, with an apparent mean elimination half-life of 88 hours in cancer patients.

Renal clearance is not a significant elimination route for netupitant-related entities. The meanfraction of an oral dose of netupitant excreted unchanged in urine is less than 1%; a total of 3.95%and 70.7% of the radioactive dose was recovered in the urine and faeces, respectively.

Approximately half the radioactivity administered orally as [14C]-netupitant was recovered fromurine and faeces within 120 h of dosing. Elimination via both routes was estimated to be complete by

Day 29-30 post-dose.

Palonosetron

Following administration of a single oral 0.75 mg dose of [14C]-palonosetron to six healthy subjects,85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in faeces.

The amount of unchanged palonosetron excreted in the urine represented approximately 40% of theadministered dose. In healthy subjects given palonosetron capsules 0.5 mg, the terminal eliminationhalf-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients, t½ was 48 ±19 hours. After a single dose of approximately 0.75 mg intravenous palonosetron, the total bodyclearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearancewas 66.5± 18.2 mL/h/kg.

Netupitant

Maximum concentrations and total exposure of netupitant were increased in subjects with mild(n=8), moderate (n=8), and severe (n=2) hepatic impairment compared to matching healthy subjects,although there was pronounced individual variability in both hepatically-impaired and healthysubjects. Exposure to netupitant (Cmax, AUC0-t and AUC0-∞) compared to matching healthy subjectswas 11%, 28% and 19% higher in mild and 70%, 88% and 143% higher in moderate hepatically-impaired subjects, respectively. As such, no dosage adjustment is necessary for patients with mild tomoderate hepatic impairment. Limited data exist in patients with severe hepatic impairment (Child

Pugh score ≥9).

Palonosetron

Hepatic impairment does not significantly affect total body clearance of palonosetron compared tothe healthy subjects. While the terminal elimination half-life and mean systemic exposure ofpalonosetron is increased in the subjects with severe hepatic impairment, this does not warrant dosereduction.

Netupitant

No specific studies were performed to evaluate netupitant in patients with renal impairment. In the

ADME trial, less than 5% of all netupitant-related material was excreted in urine and less than 1% ofthe netupitant dose was eliminated unchanged in the urine and therefore any accumulation ofnetupitant or metabolites after a single dose would be negligible. Furthermore, the population PKstudy showed no correlation between PK parameters of netupitant and markers of renal dysfunction.

Palonosetron

Mild to moderate renal impairment does not significantly affect palonosetron PK parameters. Totalsystemic exposure to intravenous palonosetron increased by approximately 28% in patients withsevere impairment relative to healthy subjects. In a population PK study, patients with a reducedcreatinine clearance (CLCR) also had a reduced palonosetron clearance, but this reduction would notresult in a significant change in palonosetron exposure.

Therefore, Akynzeo can be administered without dosage adjustment in patients with renalimpairment.

Neither netupitant nor palonosetron have been evaluated in patients with end-stage renal disease.

Palonosetron

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess ofthe maximum human exposure, indicating little relevance to clinical use. Non-clinical studiesindicate that palonosetron, only at very high concentrations, may block ion channels involved inventricular de- and re-polarisation and prolong action potential duration. Degeneration ofseminiferous epithelium was associated with palonosetron following a one month oral repeat dosetoxicity study in rats. Animal studies do not indicate direct or indirect harmful effects with respect topregnancy, embryonal/foetal development, parturition or postnatal development. Only limited datafrom animal studies are available regarding the placental transfer (see section 4.6). Palonosetron isnot mutagenic. High doses of palonosetron (each dose causing at least 15 times the humantherapeutic exposure) applied daily for two years caused an increased rate of liver tumours, endocrineneoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but not in mice.

The underlying mechanisms are not fully understood, but because of the high doses employed andsince the medicinal product is intended for single application in humans, these findings are notconsidered relevant for clinical use.

Netupitant and combination with palonosetron

Effects in non-clinical studies based on safety pharmacology and single and repeated dose toxicitywere observed only at exposures considered in excess of the maximum human exposure, indicatinglittle relevance to clinical use. Phospholipidosis (foamy macrophages) has been observed with theadministration of netupitant after repeated administration in rats and dogs. The effects werereversible or partially reversible after the recovery period. The significance of these findings inhumans is unknown.

Non-clinical studies indicate that netupitant and its metabolites and the combination withpalonosetron only at very high concentrations may block ion channels involved in ventricular de- andre-polarisation and prolong action potential duration. Reproductive studies in animals with netupitantdo not indicate direct or indirect harmful effects with respect to fertility, parturition or postnataldevelopment. An increased incidence of positional foetal abnormalities of the limbs and paws, fusedsternebrae and agenesis of accessory lung lobe were observed following daily administration ofnetupitant in rabbits at 10 mg/kg/day and higher during the period of organogenesis. In a pilot doserange finding study in rabbits, cleft palate, microphtalmia and aphakia were observed in four foetusesfrom one litter in the 30 mg/kg/day group. The relevance of these findings in humans is unknown. Nodata from animal studies with netupitant are available regarding placental transfer and lactation.

Netupitant is not mutagenic.

Hard capsule content

Netupitant tablets

Microcrystalline cellulose (E460)

Sucrose lauric acid esters

Povidone K-30

Croscarmellose sodium

Colloidal hydrated silica

Sodium stearyl fumarate

Magnesium stearate

Palonosetron soft capsules

Soft capsule content

Glycerol monocaprylocaproate (type I)

Glycerol

Polyglyceryl oleate

Purified water

Butylhydroxyanisole (E320)

Soft capsule shell

Gelatin

Glycerol

Sorbitol (E420)1,4 sorbitan

Titanium dioxide (E171)

Hard capsule shell

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Shellac glaze (partially esterified)

Black iron oxide (E172)

Propylene glycol (E1520)

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Alu/Alu blister.

Pack size of one hard capsule or 4 x1 hard capsules in perforated unit dose blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Helsinn Birex Pharmaceuticals Ltd.

Damastown

Mulhuddart

Dublin 15

Ireland.

EU/1/15/1001/001

EU/1/15/1001/002

Date of first authorisation: 27 May 2015

Date of latest renewal: 9 January 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.